This invention is in the field of non-invasive optical measuring techniques, and relates to a method for determining parameters of the patient""s blood.
Optical methods for determining blood parameters include spectrophotometric measurements, which enable the indication of the presence of various blood constituents, based on the knowledge of their spectral behavior. These methods being applied in real medicine rather than in analytical chemistry create the basis for non-invasive (in vivo) blood tests, which present, no doubt, one of today""s most exciting challenges. To make blood tests low-cost, safe and painless means to make them non-invasive.
The two main challenges, that any non-invasive optical method has to deal with, are as follows: (1) the low signal-to-noise ratio, and, (2) the large variability of individual parameters influencing the signal of concrete patients.
The main field in which the red-infrared (NIR) spectroscopy became the most widely recognized tool is the non-invasive monitoring of blood oxygenation. A pulse oximeter is the generally accepted standard of everyday clinical practice. It utilizes the so-called xe2x80x9cAC measurement techniquexe2x80x9d which focuses on measuring only the xe2x80x9cblood signalxe2x80x9d of a blood perfused tissue illuminated by a predetermined range of wavelengths.
The operation of a pulse oximeter generally consists of the following: Light passing through the patient""s finger comes out modulated by the waveform of his heartbeats. The amplitudes of this modulation for different light wavelengths contain information on the oxygen content in blood. Hence, a pulsatile component of the optical signal obtained from blood perfused tissue is utilized for determining the arterial blood oxygen saturation. In other words, the difference in light absorption of the tissue measured during the systole and the diastole phases is considered to be caused by blood that is pumped into the tissue during the systole phase from arterial vessels, and therefore has the same oxygen saturation as in the central arterial vessels.
Hence, for the AC signal, arterial blood plays the role of the key absorber. The spectral behaviors of Hb and HbO2 absorbtion differ strongly, so the oxygen saturation can be extracted from the results of the measurements. To summarize the implementation of pulse oximetry signals as carried out today, it presents oximetry as an absorption-related method based on the convolution of natural kinetics (AC/DC ratio is analysed) and spectrophotometric behavior of various ingredients. The generic limitations of this method are as follows: First, it has a rather low specificity, since only absorption variations are considered, and the scattering is treated as an inevitable obstacle (John M. Steinke, A. P. Sheperd, xe2x80x9cRole of Light Scattering in Spectrophotometric Measurements of Arteriovenous Oxygen Differencexe2x80x9d, IEEE Trans. BME-33, Aug. 8, 1986, p.729-734). Second, it has a rather low signal-to-noise ratio resulting from the low magnitude of the AC signal taken from natural blood kinetics.
When the first limitation has never been touched in practical devices (the scattering is considered to be too delicate and variable to deal with anywhere but in fundamental research), various methods have been suggested to improve the signal-to-noise ratio. Nearly all of them deal with artificially induced volumetric changes of either arterial or venous blood flow.
U.S. Pat. No. 4,883,055 discloses a method and device for artificially inducing blood pulse for use with a pulse oximeter. A cuff wrapped around a body member having an artery upstream from a testing site is adapted for applying a squeezing pulse to the body member, the squeezing pulse being synchronized with a normal blood pulse. Oxygen saturation in the arterial blood is determined based on spectrophotometric non-invasive measurements, which are effected according to the general approach of the above-mentioned AC-measurement technique.
U.S. Pat. No. 4,927,264 discloses a non-invasive apparatus and method for measuring blood constituents in venous blood. This technique utilizes the obstruction of a patient""s venous blood stream, while the arterial blood stream is not obstructed. The venous blood stream is made time-variant by applying pressure with a peak value of the minimum blood pressure to a proximal portion from a measuring part.
U.S. Pat. No. 5,638,816 discloses a blood glucose monitoring system, which provides for inducing an active pulse in the blood volume of a patient according to a predictable cyclic pattern. The induction of an active pulse causes a cyclic change in the flow of arterial blood through a fleshy medium undergoing the test. By actively inducing a change of the blood volume, modulation of the volume of blood can be obtained to provide a greater signal-to-noise ratio. This enables constituents in blood to be detected at concentration levels below those previously detectable in a non-invasive system. Radiation, which passes through the fleshy medium, is sensed by a detector which generates a signal indicative of the intensity of the detected radiation. Signal processing is performed on the electrical signal to separate those optical characteristics of the electrical signal, which are associated with the optical characteristics of the blood.
To summarize, the absolute majority of existing devices in the field of non-invasive blood measurements utilizes the natural kinetics with all its limitations in signal-to-noise ratio.
The two main limitations of the most popular non-invasive methods are connected with the interpretation based on the omission of the scattering effects that results in the low specificity of measurements, and with the utilization of natural kinetics resulting in low signal-to-noise ratio. As a result, these methods are limited by the measurement of ingredients that have highly specific spectral behavior and are present in high concentrations (as HbO2 does).
There is accordingly a need in the art to facilitate non-invasive optical measurements of various blood parameters, by providing a novel method enabling, on the one hand, the measurements with high signal-to-noise ratio, and, on the other hand, the determination of various blood parameters, also other than the oxygen saturation. These parameters may include the concentration of a substance in blood, such as glucose, hemoglobin, drugs or cholesterol, or other important blood parameters such as ESR, etc.
For blood parameters other than oxygen saturation, the determination is too problematic, because their absorption spectral behavior in red and near infrared regions is not as remarkable as for the oxygenized hemoglobin. Hence, the main limitations on the way of expanding the non-invasive techniques to the measurements different from pulse oximetry are associated with the limited selectivity of the absorption based method. In case of realistic accuracy of medical measurements for the absorption, which is not peculiar enough, the individuality of the patient becomes the main governing factor. To get rid of this limitation, scattering variations, which are more specific and sensitive than the absorption ones, have to be taken into account.
It is thus a major feature of the present invention to provide such a technique that takes into consideration both the light scattering and the light absorption in order to take into account the individual variability properly (contrary to the ideology of calibration of pulse oximeters, where light scattering is mostly ignored).
The basic idea of the invention is to combine the advantages of a high signal-to-noise ratio provided by a condition of artificial kinetics of optical characteristics (rather than natural kinetics of pulse oximetry) with high selectivity of light scattering based characteristics. The technique of the present invention is based on the convolution of spectral characteristics and artificial kinetics, and utilizes a particular kind of artificial kinetics favoring the high changes in light scattering.
The term xe2x80x9ccondition of artificial kineticsxe2x80x9d used herein signifies a state of the patient""s blood perfused fleshy medium at a measurement location, at which the parameters of the blood flow have changed in a predetermined manner, namely, at least one optical characteristic associated with the light response of blood (i.e., both absorption and scattering) has varied by a predetermined threshold value, and that the character of its change corresponds to the behavior of a time-dependent function (mostly non-periodic or, if periodic, having a period artificially imposed by the measurement system). The manner in which the changes of the blood flow parameters are obtained in order to realize the state of artificial kinetics is incorporated in both the basic physical model and digital signal processing (DSP) algorithms used in the processing of optical measurement results.
It is generally known that light scattering depends crucially on the shape of the scatterers and their optical characteristics (A. Ishimaru, xe2x80x9cWave Propagation and Scattering in Random Mediaxe2x80x9d, Vol. 1-2, Academic Press, New York, 1978). The scattering properties of blood depend on the size and shape of scatterers (aggregates). As for the absorption properties, they practically do not depend on the shape and size of scatterers, but depend almost entirely on the fraction of the components.
It has been found by the inventors that scattering assisted with erythrocyte aggregation demonstrates clearly a number of features associated with the geometry of scatterers. The difference in these features builds a theoretical basis in incorporating the light scattering characteristics in the non-invasive measurements and allowing for taking into account the individual characteristics. More specifically, it was found that light response characteristics (i.e., both absorption and scattering, but mostly scattering) of a blood perfused medium dramatically changes when a character of blood flow changes. Time changes of the light response (either monotonous or not, depending on the wavelength of incident radiation) at the condition of artificial kinetics are caused by the changes in the shape and average size of the scattering centers in the medium, i.e., red blood cells (RBC) aggregation (Rouleaux effect).
Preferably, the condition of artificial kinetics is established by creating a state of blood flow cessation at the measurement location caused by the application of over-systolic pressure at a location upstream of the measurement location with respect to the direction of normal blood flow (i.e., the so-called xe2x80x9cocclusion-based techniquexe2x80x9d). Thus, the optical characteristics of the medium start to change in time, when creating the blood flow cessation, which induces the appearance of the condition of artificial kinetics of optical characteristics: the light response (transmission) of the medium grows (either monotonically or non-monotonically) as a result of occlusion, owing to the change of the shape and average size of the scattering centers in the medium, e.g., red blood cells (RBC) aggregation, etc. Hence, the light response of the medium undergoing the occlusion can be considered as the time dependence of scattering in a system with growing scatterers.
The most straightforward result of the above technique is in signal-to-noise ratio. Once the condition of artificial kinetics is created (e.g., the blood flow cessation state is established), the optical characteristics start to change dramatically, such that they differ from those of the fleshy medium with a normal blood flow by about 25 to 45%, and sometimes even by 60%. Hence, the accuracy (i.e., signal-to-noise ratio) of the optical measurements can be substantially improved by incorporating both the artificial kinetics of light response and the spectral behavior itself. The information is extracted from the time evolutions of light responses obtained with different wavelengths of incident light following the creation of the condition of artificial kinetics (e.g., the application of over-systolic occlusion). The light responses of the medium at these wavelengths essentially differ from each other. Even the monotonicity of time evolution of light response, say at 670 nm and at 960 nm, may be different.
Thus, the state of artificial kinetics in a blood perfused fleshy medium is connected with the dramatic change of Rouleau geometry. The time variations of light responses of the medium are thus created and measured, enabling to determine a required blood parameter as a function of at least two measurable parameters. At least one of these measurable parameters is derived from scattering spectral features of the medium highly sensitive to patient individuality, i.e., a so-called Roulaue Geometry Factor (RGF). At least one other measurable parameter is indicative of artificial kinetics of the optical characteristics of the patient""s blood perfused fleshy medium, and is extracted from both the time evolution and the spectral behavior.
Thus, the present invention presents a technique for obtaining and analyzing the time changes of the spectral dependence of a light response of the patient""s blood under the condition of artificial kinetics of optical characteristics, the changes resulting from the effect of scattering on particles of different size (erythrocyte aggregates). This technique utilizes the measurement of two groups of parameters indicative of respectively, scattering spectral features of the medium highly sensitive to patient individuality, and artificial kinetics of its optical characteristics. The two parameters are used for the determination of the desired blood parameter.
The construction of the first group parameter (RGF) is associated with the following. It was found that for one wavelength of the incident radiation, the time dependence of a light response (transmission signal) asymptotically falls down, and for another wavelength it grows. RGF essentially involves the different time evolutions of light responses at different wavelengths of incident radiation. RGF may serve as one of the key-parameters for attributing the measurement results for calibration purposes. In other words, RGF is such a parameter, whose different values can characterize different groups of patients, respectively.
Preferably, the first group parameter (RGF) is a certain xe2x80x9ccut-offxe2x80x9d wavelength xcex corresponding to the transmission value T staying nearly constant with time t, namely, the wavelength corresponding to the following condition: xcex94T/xcex94t=0 (or xcex94(logT)/xcex94t=0). Alternatively, or additionally, the RGF may be a wavelength, xcexmax, corresponding to a condition under which the ratio xcex94(logT)/xcex94t as the function of wavelength xcex has its maximal value. This enables to provide an additional calibration parameter, which is specific for a certain blood condition of a specific patient. Other peculiarities (well defined mathematically) of the ratio xcex94(logT)/xcex94t as the function of wavelength and/or time t enable to characterize the blood conditions of a specific patient, which can be utilized for calibration purposes.
As for the measurable parameter indicative of the artificial kinetics (second group parameter), it is a specific function of the values of a blood parameter to be determined, specific for each patient in the group of patients characterized, say, by the common or close value of the first group parameter, and can therefore be used for determining the desired blood parameter. This second group parameter may be one of the following: parametric slopes, time increments, phase shifts in case of modulated light beams and/or occlusions.
The typical example of the second group measurable parameter is determined as a relation between the time evolutions of light responses at different wavelengths, or characteristics"" increments at the certain wavelength. This enables the explicit usage of the size of aggregates (i.e., the values that are unknown in experiments in vivo) to be eliminated.
A parametric slope is a slope of the line Txcex2(Txcex1) (or logTxcex2(LogTxcex1)), wherein Txcex2 is the time dependence of the light response (transmission) of the medium irradiated with the wavelength xcex2, and Txcex1 is the time dependence of the light response (transmission) of the medium irradiated with the wavelength xcex1. When a modulated light beam and/or modulated over-systolic pressure are applied, the phase shifts between input and output light signals may serve as the second group measurable parameters.
It should be noted that a parametric slope may actually also serve as RGF, and, consequently, may be used for calibration purposes as well. For example, the RGF may be presented in the form of a very certain combination of a few parametric slopes belonging to various time ranges of the artificial kinetics state.
There is thus provided according to the invention, a non-invasive method of optical measurements for determining at least one desired parameter of a patient""s blood, the method comprising the steps of:
(a) providing reference data indicative of the at least one desired blood parameter as a function of at least two measurable parameters, wherein one of said at least two measurable parameters is derived from scattering spectral features of the medium, and said at least one other measurable parameter is indicative of artificial kinetics of the optical characteristics of the patient""s blood perfused fleshy medium;
(b) creating a condition of the artificial kinetics and maintaining said condition for a certain time tc;
(c) illuminating a measurement location on the medium with incident light beams of different wavelengths in a red-NIR range, detecting light responses T of the medium, and generating measured data indicative of time evolutions of the light responses, T(t), of the medium for said different wavelengths, respectively, during a time period t including said certain time tc;
(d) analyzing the measured data for calculating values of said at least two measurable parameters;
(e) utilizing the calculated values and said reference data for determining a resulting value of said at least one desired blood parameter
The time tc during which the condition of the artificial kinetics is maintained is such as to enable to follow resulting change in the optical characteristics of the medium with sufficient signal-to-noise ratio.
As indicated above, the condition of artificial kinetics may be created by applying an over-systolic pressure to the patient""s blood perfused fleshy medium with a normal blood flow, so as to create a state of temporary blood flow cessation at the measurement location, and maintaining this state during a certain cessation time. The application of the over-systolic pressure may be constant during the cessation time (i.e., a single occlusion-release mode), or varying in a predetermined manner during the cessation time (i.e., a multiple occlusion-release mode). The cessation time is insufficient for irreversible changes in the fleshy medium, and may, generally, last from one second to one minute and more.
Additionally, periodical external pressure pulses of a controlled shape exceeding the systolic pressure in their maximum values, and then falling down to the normal pressure can be applied at the measurement location. This is actually the occlusion modulation procedure. This procedure may simplify drastically the processing of the measured data. Say, if the pressure pulses are strictly periodic in time, then the regular procedure of Fourier Transform may be applied to extract the parameter associated with artificial kinetics.
The reference data presents at least one desired blood parameter as a multiple-parameter function (i.e., the function of at least two measurable parameters). Thus, the reference data may be in the form of a plurality of calibration curves, such that each curve is in the form of the at least one measurable parameter of the second group as a function of values of the at least one desired blood parameter) and different calibration curves correspond to different values of the first group parameter (RGF). The reference data may be in the form of parametric surfaces, or tables.
The time interval (of the predetermined period of time) considered in the determination of the first group parameter (RGF) is the so-called xe2x80x9casymptotic time intervalxe2x80x9d that follows an initial time interval. The initial time interval is distinguished from the asymptotic time interval in that the transmission signals more strongly change with time during this interval, as compared to that of the asymptotic time interval. The time period considered in the determination of the second group parameter (e.g., parametric slope) may be the xe2x80x9cinitial time intervalxe2x80x9d (including the time during which the condition of artificial kinetics is maintained), or the xe2x80x9casymptotic time intervalxe2x80x9d. The concrete procedure being used for measurements on a certain patient depends on the spectral position of the xe2x80x9cfar asymptoticxe2x80x9d, namely, the spectral position of a zero time derivative of the light response. This position is different for different wavelengths of incident light, and varies from patient to patient.
With regard to the different wavelengths of incident light, their number is selected so as to enable the determination of the RGF used for calibration purposes, and they include at least two wavelengths selected in accordance with the parameter to be determined. For example, if the hemoglobin concentration is to be determined, the two selected wavelengths are in those ranges, where the absorption properties of the hemoglobin and plasma are more sharply expressed, namely, 600-1000 nm and 1100-1400 nm. If the oxygen saturation is to be determined, the selected wavelengths lie in the range where the difference in the absorption of hemoglobin (Hb) and oxyhemoglobin (HbO2) are more sharply expressed, namely are in the ranges of 600-780 nm (HbO2 sensitive range) and 820-980 nm (Hb sensitive range). When dealing with the glucose concentration, the spectral ranges of 1500-1600 nm may be added to the above-mentioned range of 600-1300 nm for selecting the two wavelengths, respectively.
The analysis of the measured data may also comprise the determination of an additional measurable parameter indicative of increments of growth or decrements of decline of the light response by either exponential fits or windowed FT (or wavelet) analysis.
Having determined one of the second group measurable parameters (e.g., the parametric slope) for a specific patient, a corresponding reference data portion (e.g., calibration curve), is used for determining the desired blood parameter for the specific patient (i.e., characterized by a specific value of the first group parameter). The reference data is prepared by applying measurements of the present invention (steps (b) to (d)) and the conventional ones to different patients, and determining the first and second group parameters, and the desired blood parameter.
For the determination of oxygen saturation, generally, reference data may be prepared by applying measurements of the present invention to a specific patient, at the multiple occlusion-release mode at the blood flow cessation state in a breath hold experiment.
The method of the present invention involves both the active influence on the parameters of blood flow in the medium resulting in the artificial kinetics of the optical characteristics of the medium, and the spectrometric measurements of various time depending features. The method establishes these time varying features, their time positions, and dominating trends in between for a number of wavelengths within the spectral range of a sensor. All these factors taken together build the basic information for blood parameter measurement. Then, based on this information, appropriate processing is applied for transforming the time trends to at least one desired blood parameter (the concentration of glucose and/or hematocrit, cholesterol, erthrocyte sedimentation rate (ESR), etc.).
The method of the present invention is simple and ensures a relatively high signal-to-noise ratio because of the usage of artificial kinetics, as compared to the methods utilizing measurements based on natural kinetics (i.e., synchronized with the blood pulse). This is owing to the fact that the present invention enables the parameters of the unchanged blood sample to be determined by using two or more readings of significantly distinct amplitudes. This method also allows for extracting substantially higher amount of information, as compared to conventional methods (either invasive or non-invasive), because spectral behavior of artificial kinetics accompanying the over-systolic occlusion depends strongly on a number of blood parameters: glucose, ESR, hematocrit, etc.
Such an approach has not ever been used or suggested in the prior art. This is actually an advantageous combination of the principles of artificial kinetics offering a high signal to noise ratio, and scattering assisted spectral peculiarities offering high sensitivity to patient""s individual features.
As indicated above, the optical characteristics of a blood perfused fleshy medium at the state of blood flow cessation differ from those of the fleshy medium with normal blood flow by about 25 to 45%, and sometimes even by 60%. Conventional methods of pulse oximetry make use of fluctuations of light transmitting characteristics in the range of about 2%.
Since the novel method enables to obtain a spectrum of readings differing from each other by up to 60%, more than two sessions may be chosen for effecting the measurements and for further statistical processing of the obtained results. Additionally, it has been found that the method effects an extremely high correlation between values of the concentration obtained from the measurements. Hence, determining of concentration may comprise comparison and cross-validation of the results obtained from two or more measurements. The comparison and cross-validation may include the calculation of the average and a statistical procedure of standard deviation values. Information about a statistical error in a specific measurement may be of a great importance for a physician or a customer.
The method is preferably intended for measuring the concentration of chemical or biological substances, which are present in the blood, regardless of the character of its flow. It should, however, be noted that the method can also be used for determining blood oxygen saturation and/or other parameters that depend on the existence of a normal blood pulse, provided additional conditions and approximations are taken into consideration.
The inventive method can be used both for independent measurements and for calibration of other non-invasive methods intended for obtaining similar data and based on measurements synchronized with the blood pulse, for example, methods for the continuous monitoring of blood parameters at departments of intensive care in hospitals.